Before blaming SARS-CoV-2 for venous sinus thrombosis in a septic patient, consider alternative etiologies

Letter to the editor

We read with interest the article by Arga et al. on a 40 day old male who was diagnosed with septic shock and cerebral venous sinus thrombosis (CVST) without identifying an infectious agent other than SARS-CoV-2 by PCR on a naso-pharyngeal swab test but not in the cerebrospinal fluid (CSF) [1]. Upon empirical antibiotic treatment and low-molecular weight heparin (LMWH) the patient recovered neurologically completely [1]. The study is appealing but carries limitations that raise concerns and should be discussed.

The main limitation of the study is that a causal relation between SARS-CoV-2 and CVST could not be established. The patient had neither pulmonary nor gastro-intestinal manifestations of a SARS-CoV-2 infection. The CSF was negative for SARS-CoV-2. The mother of the child was also negative for SARS-CoV-2. No titres of neutralizing antibodies were measured. It has not been considered and ruled out that the infection occurred inside the hospital and has to be actually interpreted as superinfection. A false positive result of the PCR test was not considered either [2]. A further argument against causality between SARS-CoV-2 and CVST is that the patient had severe sepsis, which could have favoured CVST as well.

Another limitation is that the cause of sepsis could not be clarified [1]. Readers should know if there was eosinophilia, if IgE levels were elevated, or if blood or CSF cultures for fungi were carried out. It is crucial to rule out a fungal infection. An argument against SARS-CoV-2 as the cause of sepsis is that the patient had granulocytosis but not lymphocytosis. Further arguments against SARS-CoV-2 as the cause of sepsis are that the virus has been discussed as the cause of sepsis but has not been confirmed as such [3] and that SARS-CoV-2 favours superinfections.

A further limitation of the study is that no results of multimodal cerebral MRI were provided [1]. CVST is often complicated by seizures, ischemic stroke or bleeding. These neurological abnormalities should be ruled out before concluding that the patient had no neurological manifestations other than CVST. Because the patient was lethargic, restless, and sleepy, results of multimodal cerebral MRI with contrast medium are mandatory to rule out encephalitis, ventriculitis, and stroke. Encephalitis may be present even in the absence of pleocytosis [4] and the only abnormal CSF finding may be elevated CSF protein, as in the index patient [1].

Referring to the proBNP value of 5699pg/ml and transthoracic echocardiography, the index patient had heart failure but the explanation - septic shock - is not satisfactory. Particularly, in the light of elevated troponin and CK-MB, myocardial damage should be considered and readers should know if endocarditis, myocarditis, Takotsubo syndrome (TTS), or myocardial infarction were appropriately ruled out. Of particular interest is if the patient underwent cardiac MRI with contrast medium or endomyocardial biopsy and if coronary angiography had been performed. TTS has been repeatedly reported as a complication of sepsis [5] respectively SARS-CoV-2 infections [6].

A further limitation is that pulmonary embolism was not considered and had not been ruled out appropriately. Because the patient had tachypnoea, CVST, jugular vein thrombosis, a normal X-ray of the lungs, elevated d-dimer, and sepsis, it is obligatory that pulmonary embolism had been ruled out.

Another shortcoming of the study is that reference limits were not provided for most of the parameters. However, if applying our own reference limits, several parameters were out of normal range. Accordingly, it is not comprehensible why normal saline was infused although the patient had hypernatriemia. There is also no explanation provided for lactic acidosis. We should know if it was attributed to sepsis, seizures, or if the patient had a mitochondrial disorder. An explanation should be provided why the patient did not have headache or epilepsy, frequent manifestations of a CVST.

Overall, the interesting study has limitations that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the study. The cause of sepsis should be identified to adequately treat it and in a septic patient with altered mental state encephalitis and ventriculitis should be ruled out.

Funding

No funding was received.

Data access statement

All data are available from the corresponding author.

Ethics statement

Not applicable.

Author contribution

JF: design, literature search, discussion, first draft, critical comments, final approval.

Disclosures

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data access statement

Not applicable.

Compliance with ethics guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.